Therapeutic targeting of TREM2 for Alzheimer's disease

TREM2 治疗阿尔茨海默病的靶向治疗

基本信息

批准号：
9423846
负责人：
Donna M Wilcock
金额：
$ 187.83万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-01 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9423846
关键词：
APP-PS1 Abeta clearance Acute Adverse event Alzheimer&apos s Disease Amyloid Amyloid beta-Protein Amyloid deposition Antibodies Biochemistry Cell Separation Cerebral Amyloid Angiopathy Chronic Clinic Cognition Cognitive Comorbidity Deposition Disease Disease Pathway Genes Genetic Population Study Genetic study Goals Histology Hyperhomocysteinemia Image Immune Immunohistochemistry Immunologic Receptors Immunotherapy Impairment Inflammatory Response Innate Immune System Magnetic Resonance Imaging Mediating Methods Microglia Modeling Mus Myeloid Cells Names Nerve Degeneration Neurofibrillary Tangles Pathology Phagocytosis Risk Signal Transduction TREM2 gene TYROBP gene Tauopathies Testing Tg2576 Therapeutic Time Transgenic Mice Translations Vascular Cognitive Impairment aged amyloid pathology base behavior test cerebrovascular cerebrovascular pathology design effective therapy genome wide association study immunoregulation improved intraperitoneal loss of function mouse model nano-string neuroinflammation neuroprotection new therapeutic target novel pre-clinical prevent receptor response risk variant targeted treatment tau Proteins therapeutic target vasogenic edema

项目摘要

ABSTRACT The identification of novel therapeutic targets for Alzheimer's disease is necessary to reach the goal of the National Alzheimer's Project Act (NAPA) of having an effective treatment in place by 2025. Despite numerous promising therapeutic approaches identified pre-clinically to treat Alzheimer's disease, the translation of these therapies to the clinic have been incredibly disappointing. The vast number of population genetic studies that have been performed for AD present an opportunity to identify disease pathways what could be targeted therapeutically. One gene that has a strong effect on AD risk is the triggering receptor expressed on myeloid cells-2 (TREM2). As the name implies, TREM2, is an innate immune receptor expressed on microglia, known to signal through DAP12 to trigger phagocytosis. TREM2 SNPs have been identified as significantly increasing risk of AD in GWAS studies. The hypothesis for this increased risk is that there is a loss of function, impairing the innate immune system to clear amyloid deposition efficiently. We hypothesize that targeting TREM2 to activate the receptor will modulate the neuroinflammatory response and stimulate microglia to phagocytose and clear the amyloid deposits. Furthermore, we hypothesize that activating the TREM2 receptor to modulate the neuroinflammatory response will ameliorate tau pathology, provide neuroprotection, and avoid cerebrovascular adverse events associated with Aβ targeted therapies. To activate the TREM2 receptor, we are using an antibody developed by Alector, LLC, Alector-002a, that recognizes TREM2 and activates the receptor. We have found that the antibody show immune modulation, clearance of amyloid deposits, and cognitive improvement in amyloid depositing mice. We propose three specific aims to test our hypothesis: Specific Aim 1: Determine the neuroinflammatory, amyloid lowering and cognitive effects of A-002a. Specific Aim 2: Determine the tau modifying, neuroprotective and cognitive effects of A-002a. Specific Aim 3: Determine the potential for cerebrovascular adverse events of A-002a.

抽象的必须鉴定阿尔茨海默氏病的新型治疗靶标对于达到目标的目标是必要的国家阿尔茨海默氏症的项目法案（NAPA）到2025年进行有效的治疗。尽管有很多在临时治疗阿尔茨海默氏病之前，有希望的治疗方法，这些方法的翻译诊所的疗法令人难以置信。大量的人口遗传研究已经对广告进行了识别疾病途径的机会剧院。一个对AD风险具有很强作用的基因是在髓样中表达的触发受体细胞2（TREM2）。顾名思义，trem2是一种先天免疫受体，在小胶质细胞上表达，已知通过DAP12发出信号以触发吞噬作用。 TREM2 SNP已被确定为显着增加 GWAS研究中的广告风险。这种增加风险的假设是功能丧失，损害先天免疫系统有效清除淀粉样蛋白沉积。我们假设将trem2靶向激活受体将调节神经炎症反应并刺激小胶质细胞吞噬细胞并清除淀粉样蛋白沉积物。此外，我们假设激活trem2 调节神经炎症反应的受体将改善tau病理，提供神经保护，避免与Aβ靶向疗法相关的脑血管不良事件。到激活Trem2受体，我们使用了Alector，LLC，Alector-002a开发的抗体，识别TREM2并激活接收器。我们发现抗体显示免疫调节，淀粉样蛋白沉积物的清除和淀粉样蛋白沉积小鼠的认知改善。我们提出了三个特定的目的是检验我们的假设：特定目标1：确定A-002A的神经炎症，淀粉样蛋白降低和认知作用。特定目标2：确定A-002A的TAU修饰，神经保护作用和认知效应。具体目标3：确定A-002A的脑血管不良事件的潜力。